Anthracyclin antibiotics are a class of aromatic polyketides, and are pigment glycosides composed of an aglycon moiety, of which the basic skeleton is 7,8,9,10-tetrahydro-5,12-naphthacenequinone with the following chemical formula, and a sugar moiety, which is mainly composed of amino sugar(s).

Anthracyclin antibiotics bind with DNA and generate radicals, which cleave the DNA strands or inhibit topoisomerase II. Topoisomerase has a DNase activity and a ligase activity, and catalyzes the transient cleavage of DNA strands and the religation thereof. Anthracyclin antibiotics damage DNA replication by inhibiting topoisomerase II, and exert their antitumor activity. The anthracyclin antibiotics have accumulated cardiac toxicity, but are considered to be an effective antitumor drug because of their wide spectrum of antitumor activity.
Anthracyclin antitumor drugs that are currently used include compounds, such as daunorubicin, which are derived from fermentation products, and semi-synthetic products such as doxorubicin or epirubicin, which are produced from daunorubicin as a starting material.

TABLE 1R1R2R3DaunorubicinCH3HOHDoxorubicinCH2OHHOHEpidaunorubicinCH3OHHEpirubicinCH2OHOHH
Epirubicin is superior to daunorubicin and doxorubicin in antitumor activity and toxicity, but has disadvantages in production cost. This is because epirubicin is produced from daunorubicin as a starting material, but the process includes a chemical synthesis step of reversing the hydroxyl group at 4-position of the amino sugar moiety with a low yield.
It was reported that a gene encoding a ketoreductase (epi-type ketoreductase), different in the stereospecificity of products from a ketoreductase involved in the biosynthesis of daunorubicin, was introduced into a daunorubicin-producing bacterium, and the biosynthesis pathway of daunorubicin was modified to produce epidaunorubicin by direct fermentation (non-patent literature 1). Epidaunorubicin has the same conformation of the hydroxyl group of the amino sugar moiety as epirubicin, and thus, epidaunorubicin can be used as an extremely useful starting material for the production of epirubicin. It was reported that when the epi-type ketoreductase gene (avrE) involved in the biosynthesis of avermectin was introduced, the transformant produced the largest amount of epidaunorubicin. However, the amount produced was only approximately 54 μg/mL, which did not reach a practically usefule level.
Further, a patent application in which the epidaunorubicin-producing bacterium obtained in non-patent literature 1 was treated with a mutagen to increase the productivity of epidaunorubicin to 100 μg/mL or more was filed (patent literature 1), but the obtained mutant was not described in detail in the Examples.    [patent literature 1] International Publication No. WO 2006/111561 A1    [non-patent literature 1] Madduri, K. et al., Nature Biotechnology, (U.S.A.), 1998, vol. 16, p. 69-74